ERBB2 overexpression suppresses stress-induced autophagy and renders ERBB2-induced mammary tumorigenesis independent of monoallelic Becn1 loss.
Defective autophagy has been implicated in mammary tumorigenesis, as the gene encoding the essential autophagy regulator BECN1 is deleted in human breast cancers and Becn1(+/-) mice develop mammary hyperplasias. In agreement with a recent study, which reports concurrent allelic BECN1 loss and ERBB2 amplification in a small number of human breast tumors, we found that low BECN1 mRNA correlates with ERBB2-overexpression in breast cancers, suggesting that BECN1 loss and ERBB2 overexpression may functionally interact in mammary tumorigenesis. We now report that ERBB2 overexpression suppressed autophagic response to stress in mouse mammary and human breast cancer cells. ERBB2-overexpressing Becn1(+/+) and Becn1(+/-) immortalized mouse mammary epithelial cells (iMMECs) formed mammary tumors in nude mice with similar kinetics, and monoallelic Becn1 loss did not alter ERBB2- and PyMT-driven mammary tumorigenesis. In human breast cancer databases, ERBB2-expressing tumors exhibit a low autophagy gene signature, independent of BECN1 mRNA expression, and have similar gene expression profiles with non-ERBB2-expressing breast tumors with low BECN1 levels. We also found that ERBB2-expressing BT474 breast cancer cells, despite being partially autophagy-deficient under stress, can be sensitized to the anti-ERBB2 antibody trastuzumab (tzb) by further pharmacological or genetic autophagy inhibition. Our results indicate that ERBB2-driven mammary tumorigenesis is associated with functional autophagy suppression and ERBB2-positive breast cancers are partially autophagy-deficient even in a wild-type BECN1 background. Furthermore and extending earlier findings using tzb-resistant cells, exogenously imposed autophagy inhibition increases the anticancer effect of trastuzumab on tzb-sensitive ERBB2-expressing breast tumor cells, indicating that pharmacological autophagy suppression has a wider role in the treatment of ERBB2-positive breast cancer.
Rutgers University; State University of New Jersey; New Brunswick, NJ USA; Rutgers Cancer Institute of New Jersey; New Brunswick, NJ USA.
Fred
F
Lozy
Rutgers University; State University of New Jersey; New Brunswick, NJ USA; Rutgers Cancer Institute of New Jersey; New Brunswick, NJ USA.
Xiaofeng
X
Cai-McRae
Rutgers University; State University of New Jersey; New Brunswick, NJ USA; Rutgers Cancer Institute of New Jersey; New Brunswick, NJ USA.
Irina
I
Teplova
Rutgers University; State University of New Jersey; New Brunswick, NJ USA; Rutgers Cancer Institute of New Jersey; New Brunswick, NJ USA.
Sandy
S
Price
Rutgers University; State University of New Jersey; New Brunswick, NJ USA.
Anupama
A
Reddy
Rutgers University; State University of New Jersey; New Brunswick, NJ USA; Rutgers Cancer Institute of New Jersey; New Brunswick, NJ USA.
Gyan
G
Bhanot
Rutgers University; State University of New Jersey; New Brunswick, NJ USA; Rutgers Cancer Institute of New Jersey; New Brunswick, NJ USA; Division of Medical Oncology; Department of Internal Medicine; Rutgers Robert Wood Johnson Medical School; Piscataway, NJ USA.
Shridar
S
Ganesan
Rutgers University; State University of New Jersey; New Brunswick, NJ USA; Rutgers Cancer Institute of New Jersey; New Brunswick, NJ USA.
Alexei
A
Vazquez
Rutgers University; State University of New Jersey; New Brunswick, NJ USA; Rutgers Cancer Institute of New Jersey; New Brunswick, NJ USA; Division of Medical Oncology; Department of Internal Medicine; Rutgers Robert Wood Johnson Medical School; Piscataway, NJ USA.
Vassiliki
V
Karantza
D000818:Animals; D061067:Antibodies, Monoclonal, Humanized / Q000494:pharmacology; D051017:Apoptosis Regulatory Proteins / Q000172:deficiency; D001343:Autophagy / Q000187:drug effects* / Q000235:genetics; D000071186:Beclin-1; D001943:Breast Neoplasms / Q000378:metabolism* / Q000473:pathology; D002471:Cell Transformation, Neoplastic / Q000378:metabolism; D005260:Female; D006801:Humans; D008321:Mammary Glands, Animal / Q000378:metabolism; D008565:Membrane Proteins / Q000172:deficiency; D051379:Mice; D008822:Mice, Transgenic; D018719:Erb-b2 Receptor Tyrosine Kinases / Q000378:metabolism*; D015398:Signal Transduction / Q000187:drug effects / Q000276:immunology; D013312:Stress, Physiological / Q000502:physiology*; D000068878:Trastuzumab
D061067:Antibodies, Monoclonal, Humanized; D051017:Apoptosis Regulatory Proteins; D000071186:Beclin-1; D008565:Membrane Proteins; D018719:Erb-b2 Receptor Tyrosine Kinases; D000068878:Trastuzumab; C491997:BECN1 protein, human; C115010:Becn1 protein, mouse
ERBB2; MMTV-Neu; MMTV-PyMT; autophagy; breast cancer; trastuzumab