In recognition of Hereditary Breast and Ovarian Cancer Week, Focus on Cancer is highlighting new support and research efforts for male carriers of BRCA mutations.

In August, the Philadelphia Inquirer reported an increase in research and support, specifically for male carriers of BRCA1/2 mutations. These mutations are known for being strong indicators of breast and ovarian cancer risk; as well as other types of cancer.

“Men very much matter in this equation,” said Jacquelyn Powers, MS, CGC, a genetic counselor at Penn’s Basser Research Center for BRCA, during her presentation at a recent conference in Philadelphia with partner organization, FORCE.

Understanding Hereditary Cancer Risk for Male Carriers

In men, mutations in either gene raise the risk for breast cancer as well as risk for other cancers. In fact, men with BRCA1 mutations have between a 1-5% lifetime risk of breast cancer and men with BRCA2 mutation have between a 5-10% lifetime risk of breast cancer.

Typically, a man’s risk of breast cancer is 0.1%, or 1 in 1,000. Men who carry a BRCA mutation may also have an increased risk of prostate cancer, melanoma and pancreatic cancer.

Men, as well as women, can inherit and pass on a BRCA mutation to their children, further driving the demand for new research and support.

Penn Investigators Take Leading Role in Research 

In one international study, investigators from Penn are exploring the best way to screen male carriers with increased prostate cancer risk. Men with BRCA1/2 mutations who develop prostate cancer tend to develop these cancers at an earlier age than average and may develop more aggressive forms of the disease.

Free Webinar for Male BRCA Carriers with Basser and FORCE 10/1

Recent studies of the interferon-induced transcription factor STAT1 have associated its dysregulation with poor prognosis in some cancers, but its mechanistic contributions are not well defined. In this study, we report that the STAT1 pathway is constitutively upregulated in type II endometrial cancers. STAT1 pathway alteration was especially prominent in serous papillary endometrial cancers (SPEC) that are refractive to therapy. Our results defined a “SPEC signature” as a molecular definition of its malignant features and poor prognosis. Specifically, we found that STAT1 regulated MYC as well as ICAM1, PD-L1, and SMAD7, as well as the capacity for proliferation, adhesion, migration, invasion, and in vivo tumorigenecity in cells with a high SPEC signature. Together, our results define STAT1 as a driver oncogene in SPEC that modulates disease progression. We propose that STAT1 functions as a prosurvival gene in SPEC, in a manner important to tumor progression, and that STAT1 may be a novel target for molecular therapy in this disease. Cancer Res; 74(22); 1–12. ©2014 AACR.

Recent studies of the interferon-induced transcription factor STAT1 have associated its dysregulation with poor prognosis in some cancers but its mechanistic contributions are not well defined. In this study, we report that the STAT1 pathway is constitutively upregulated in type II endometrial cancers. STAT1 pathway alteration was especially prominent in serous papillary endometrial cancers (SPEC) that are refractive to therapy. Our results defined a ‘SPEC signature’ as a molecular definition of its malignant features and poor prognosis. Specifically, we found that STAT1 regulated MYC as well as ICAM1, PD-L1, and SMAD7 as well as the capacity for proliferation, adhesion, migration, invasion, and in vivo tumorigenecity in cells with a high SPEC signature. Together our results define STAT1 as a driver oncogene in SPEC that modulates disease progression. We propose that STAT1 functions as a pro-survival gene in SPEC, in a manner important to tumor progression, and that STAT1 may be a novel target for molecular therapy in this disease-

CD98hc (SLC3A2) is the heavy chain component of the dimeric transmembrane glycoprotein CD98, which comprises the large neutral amino acid transporter LAT1 (SLC7A5) in cells. Overexpression of CD98hc occurs widely in cancer cells and is associated with poor prognosis clinically, but its exact contributions to tumorigenesis are uncertain. In this study, we showed that genetic deficiency of CD98hc protects against Ras-driven skin carcinogenesis. Deleting CD98hc after tumor induction was also sufficient to cause regression of existing tumors. Investigations into the basis for these effects defined two new functions of CD98hc that contribute to epithelial cancer beyond an intrinsic effect of CD98hc on tumor cell proliferation. First, CD98hc increased the stiffness of the tumor microenvironment. Second, CD98hc amplified the capacity of cells to respond to matrix rigidity, an essential factor in tumor development. Mechanistically, CD98hc mediated this stiffness sensing by increasing Rho kinase (ROCK) activity, resulting in increased transcription mediated by YAP/TAZ, a nuclear relay for mechanical signals. Our results suggest that CD98hc contributes to carcinogenesis by amplifying a positive feedback loop, which increases both extracellular matrix stiffness and resulting cellular responses. This work supports a rationale to explore the use of CD98hc inhibitors as cancer therapeutics. Cancer Res; 74(23); 1–12. ©2014 AACR.

CD98hc (SLC3A2) is the heavy chain component of the dimeric transmembrane glycoprotein CD98, which comprises the large neutral amino acid transporter LAT1 (SLC7A5) in cells. Overexpression of CD98hc occurs widely in cancer cells, and is associated with poor prognosis clinically, but its exact contributions to tumorigenesis are uncertain. In this study, we showed that that genetic deficiency of CD98hc protects against Ras-driven skin carcinogenesis. Deleting CD98hc after tumor induction was also sufficient to cause regression of existing tumors. Investigations into the basis for these effects defined two new functions of CD98hc that contribute to epithelial cancer beyond an intrinsic effect on CD98hc on tumor cell proliferation. First, CD98hc increased the stiffness of the tumor microenvironment. Second, CD98hc amplified the capacity of cells to respond to matrix rigidity, an essential factor in tumor development. Mechanistically, CD98hc mediated this stiffness-sensing by
increasing Rho kinase (ROCK) activity, resulting in increased transcription mediated by YAP/TAZ, a nuclear relay for mechanical signals. Our results suggest that CD98hc contributes to carcinogenesis by amplifying a positive feedback loop which increases both extracellular matrix stiffness and resulting cellular responses. This work supports a rationale to explore the use of CD98hc inhibitors as cancer therapeutics